Alzheimer's disease (AD) is the most common type of dementia in aging adults with the number of people living with AD projected to increase dramatically over the next few decades, making the search for treatments and tools to diagnose and measure disease progression increasingly urgent.
Approved treatments are few and of limited efficacy, serving mostly to slow or delay progression. Currently there is no cure.
AD gives rise to an irreversible progressive loss of cognitive functions and of functional autonomy. While the time it takes for AD to develop will vary from person to person, advanced signs include severe memory impairment, confusion, language disturbances, impaired judgment, personality and behaviour changes. Patients with AD may become non-communicative and hostile. As the disease ends its course in profound dementia, patients are unable to care for themselves and often require institutionalization or professional care in the home setting. While some patients may live for many years after being diagnosed with AD, the average life expectancy after diagnosis is eight years.
Although AD can only be definitively diagnosed by brain biopsy or upon autopsy after a patient died, in clinical settings brain biopsy is rarely performed and diagnosis is still primarily made based on the history of the symptoms and depends on a battery of neurological, psychometric and biochemical tests, which include the measurement of biomarkers.
Nevertheless, these present methods are still not satisfactory in the diagnosing of AD and other neurocognitive disorders at the early stage of the disease when potential therapies are more likely to prevent or slow down neurodegeneration.
As the brain is in direct contact with the cerebrospinal fluid (CSF), and pathological changes in the brain often result in altered biochemical composition of the CSF, this makes it an ideal source for biomarkers of neurocognitive disorders. In AD, currently three “core” CSF biomarkers (amyloid β1-42, total tau and phosphorylated tau) are routinely used to diagnose AD. All three of these CSF biomarkers demonstrate high levels of sensitivity (falling within the 80-90% criteria specified by the National Institute of Neurological and Disorders and Stroke and the Alzheimer Disease and Related Disorders Work Group) but struggle to differentiate AD from other forms of dementia and neurological disorders. For example, CSF amyloid β1-42 levels are decreased in AD but are also reportedly lower in Lewy body dementia (LBD), fronto-temporal dementia (FTD), vascular dementia (VaD), amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease (CJD) (Blennow K et al., Nat Rev Neurol. 2010, 6:131-44). Similarly, total tau levels are raised in AD but are also found elevated following stroke, traumatic brain injury, FTD, VaD and CJD1.
Two key features of an ideal biomarker are high specificity for disease versus non-disease and high sensitivity to distinguish between disease types. In addition, biomarkers that reflect the pathological process of AD and that are able to detect changes at a very early stage of the disease, before degeneration is observed by brain imaging and neuropathological tests, are very sought after.
The ideal biomarker or biomarker panel would be the first indicator for starting treatment as early as possible, when degeneration is still limited, it would prove immensely valuable in screening the effectiveness of new therapies in clinical trial settings, particularly those trials that are focused on preventing the development of neuropathological changes. Such biomarker or biomarker panel would also be useful in the follow-up of the development of the disease.
Hence, there remains a need for biomarkers that may perform with superior sensitivity and/or specificity in the early diagnosis, staging and prognostic monitoring of patients with Alzheimer's disease and other neurocognitive disorders.